Acute myocardial infarction is the leading cause of morbidity and mortality in industrialized countries. Ischemic postconditioning, that consists of repeated brief episodes of ischemia-reperfusion performed just after reflow following a prolonged ischemic insult, dramatically reduces infarct size in animal models. Recent data indicate that it might involve the activation of the PI3-kinase—Akt—eNOS as well as PKC signalling pathways and inhibition of the opening of the permeability transition pore. A recent clinical study demonstrated that postconditioning protects the human heart. Repeated brief episodes of inflation-deflation of the angioplasty balloon performed immediately after re-opening of the culprit coronary artery reduced infarct size by 36%. Additional studies are required to determine whether infarct size limitation by postconditioning would improve functional recovery as well as patient’s outcome. Further research is needed to find new pharmacological agents that would mimick postconditioning in order to treat all patients with ongoing acute myocardial infarction.